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Abstract:

The present invention relates to cyclohexyloxy-substituted heterocycles
of general formula (I)
##STR00001##
the tautomers, the stereoisomers, the mixtures thereof and the salts
thereof, particularly the physiologically acceptable salts thereof with
inorganic or organic acids, which have valuable pharmacological
properties, particularly an inhibitory effect on signal transduction
mediated by tyrosine kinases, the use thereof for the treatment of
diseases, particularly tumoral diseases as well as benign prostatic
hyperplasia (BPH), diseases of the lungs and airways and the preparation
thereof.

Claims:

1. A compound of formula (I) ##STR00047## wherein: Ra denotes a
phenyl or 1-phenylethyl group, wherein the phenyl nucleus is substituted
in each case by the groups R1 to R3, wherein R1 and
R2 which may be identical or different, denote hydrogen or a group
selected from among F, Cl, Br, I, OCH2F, OCHF2, OCF3,
CH2F, CHF2, CF3, CN, NO2, NH2 and OH, or a group
selected from among C1-4-alkyl, C1-4-alkyl-O,
C2-3-alkenyl, C2-3-alkynyl, phenyl, phenyl-O,
phenyl-C1-3-alkyl, phenyl-C1-3-alkyl-O, heteroaryl,
heteroaryl-O, heteroaryl-C1-3-alkyl, heteroaryl-C1-3-alkyl-O,
wherein the above-mentioned phenyl groups are mono- or disubstituted by
R5 groups, and R3 denotes hydrogen, or a group selected from
among F, Cl, Br and CH3, Rb denotes hydrogen, or an optionally
substituted group selected from among C1-6-alkyl,
C3-6-cycloalkyl and C3-6-cycloalkyl-C1-3-alkyl, Rc
denotes hydrogen, or an optionally substituted group selected from among
C1-6-alkyl, C3-6-cycloalkyl,
C3-6-cycloalkyl-C1-3-alkyl, C1-6-alkyl-CO,
C3-6-cycloalkyl-CO, C3-6-cycloalkyl-C1-3-alkyl-CO,
C1-6-alkyl-SO2, C3-6-cycloalkyl-SO2,
C3-6-cycloalkyl-C1-3-alkyl-SO2, phenyl-CO-- and
phenyl-SO2, Rd denotes hydrogen or a group selected from among
F, Cl, Br, I, OH, C1-4-alkyl, C1-4-alkyl-O, C1-2-alkyl-O
substituted by 1 to 3 fluorine atoms, C3-7-cycloalkyl-O,
C3-7-cycloalkyl-C1-4-alkyl-O, tetrahydrofuran-3-yl-O,
tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl-O,
tetrahydrofuranyl-C1-4-alkyl-O-- and
tetrahydropyranyl-C1-4-alkyl-O, or R4--C1-4-alkyl, wherein
the linking of the groups R4 may take place via each C atom of the
alkyl group, or R4--C2-4-alkyl-O, wherein the group R4 is
separated from the oxygen atom by at least 2 C atoms, or a group selected
from among pyrrolidin-2-yl-C1-4-alkyl-O,
pyrrolidin-3-yl-C1-4-alkyl-O, piperidin-2-yl-C1-4-alkyl-O,
piperidin-3-yl-C1-4-alkyl-O, piperidin-4-yl-C1-4-alkyl-O,
azepan-2-yl-C1-4-alkyl-O, azepan-3-yl-C1-4-alkyl-O,
azepan-4-yl-C1-4-alkyl-O, morpholin-2-yl-C1-4-alkyl-O,
morpholin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-pyrrolidin-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-pyrrolidin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-4-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-4-yl-C1-4-alkyl-O,
4-(C1-3-alkyl)-morpholin-2-yl-C1-4-alkyl-O and
4-(C1-3-alkyl)-morpholin-3-yl-C1-4-alkyl-O, wherein R4
denotes a group, which may be identical or different, selected from among
OH, C1-3-alkyl-O, C3-6-cycloalkyl-O, NH2,
C1-3-alkyl-NH, (C1-3-alkyl)2N, (2-methoxyethyl)2N,
pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl,
1,4-oxazepan-4-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,
3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl,
piperazin-1-yl, 4-(C1-3-alkyl)-piperazin-1-yl, 1,4-diazepan-1-yl,
4-(C1-3-alkyl)-1,4-diazepan-1-yl, HCO--NH, C1-4-alkyl-CO--NH,
C1-3-alkyl-O--C1-3-alkyl-CO--NH, C1-4-alkyl-O--CO--NH,
H2NCONH, C1-3-alkyl-NH--CO--NH, (C1-3-alkyl)2N--CONH,
pyrrolidin-1-yl-CO--NH, piperidin-1-yl-CO--NH, piperazin-1-yl-CO--NH,
4-(C1-3-alkyl)-piperazin-1-yl-CO--NH, morpholin-4-yl-CO--NH and
C1-4-alkyl-SO2--NH, wherein the pyrrolidinyl, piperidinyl,
azepan-1-yl, piperazinyl, 1,4-diazepan-1-yl, morpholinyl and
1,4-oxazepan-4-yl groups mentioned above in the definition of the group
Rd may each additionally be substituted by one or two
C1-3-alkyl groups, and wherein the above-mentioned phenyl groups is
mono- or disubstituted by R5 groups, wherein R5 denotes
hydrogen, or a group, which may be identical or different, selected from
among F, Cl, Br, I, OH, CN, C1-3-alkyl, C1-3-alkyl-O,
CHF2, CF3, --O--CHF2 and --O--CF3, and unless stated
otherwise, the above-mentioned alkyl groups may be straight-chain or
branched, A denotes --CO or --C1-C3-alkylene, wherein the
--C1-C3-alkylene group may be 1-, 2-, 3- or 4-substituted by a
group R6, and R6 which may be identical or different, denotes
hydrogen, or a group selected from among OH, C1-C4-alkyl and
--O--C1-C4-alkyl, optionally in the form of the tautomers, the
racemates, the enantiomers, the diastereomers and the mixtures thereof,
and optionally the pharmacologically acceptable acid addition salts
thereof.

2. The compounds according to claim 1, wherein: Ra denotes a group
selected from among 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl,
5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl,
2-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl and
3-chloro-2-methyl-phenyl group, Rb and Rc which may be
identical or different, denote hydrogen or C1-3-alkyl, Rd
denotes C1-3-alkyl-O, unless stated otherwise, the above-mentioned
alkyl groups may be straight-chain or branched, A denotes
--CH2CH2, wherein the --CH2CH2-- group may be
substituted by 1 or 2 methyl groups, optionally in the form of the
tautomers, the racemates, the enantiomers, the diastereomers and the
mixtures thereof, and optionally the pharmacologically acceptable acid
addition salts thereof.

3. (canceled)

4. A method for the treatment of inflammatory or allergic diseases of the
airways comprising administering to a patient in need thereof a
therapeutically effective amount of a compound according to claim 1 or a
pharmacologically acceptable acid addition salt thereof.

6. The method according to claim 4, characterised in that it relates to
inflammatory or allergic conditions in which autoimmune reactions are
involved.

7. A method for the treatment of benign or malignant tumours comprising
administering to a patient in need thereof a therapeutically effective
amount of a compound according to claim 1 or a pharmacologically
acceptable acid addition salt thereof.

8. A pharmaceutical formulation containing a compound of formula (I)
according to claim 1.

9. An orally administered pharmaceutical formulation according to claim
8.

10. A medicament combinations which contains, besides one or more
compounds of formula (I) according to claim 1, as further active
substances, one or more compounds selected from among the categories of
betamimetics, anticholinergics, corticosteroids, further PDE4-inhibitors,
LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines,
PAF-antagonists and PI3-kinase inhibitors or double or triple
combinations thereof.

Description:

[0001] The present invention relates to cyclohexyloxy-substituted
heterocycles of general formula

##STR00002##

the tautomers, the stereoisomers, the mixtures thereof and the salts
thereof, particularly the physiologically acceptable salts thereof with
inorganic or organic acids, which have valuable pharmacological
properties, particularly an inhibitory effect on signal transduction
mediated by tyrosine kinases, the use thereof for the treatment of
diseases, particularly tumoral diseases as well as benign prostatic
hyperplasia (BPH), diseases of the lungs and airways and the preparation
thereof.

[0002] The problem of the present invention is to prepare new compounds
which on the basis of their pharmaceutical effectiveness as
tyrosine-kinase inhibitors, may be used therapeutically, i.e. for the
treatment of pathophysiological processes caused by hyperfunction of
tyrosine kinases.

DETAILED DESCRIPTION OF THE INVENTION

[0003] It has surprisingly been found that the problem mentioned above is
solved by compounds of formula (I), wherein the groups Ra to Rd
and A have the meanings given hereinafter. The present invention
therefore relates to compounds of general formula (I),

##STR00003##

wherein [0004] Ra denotes a phenyl or 1-phenylethyl group, wherein
the phenyl nucleus is substituted in each case by the groups R1 to
R3, where [0005] R1 and R2 which may be identical or
different, denote hydrogen or a group selected from among [0006] F, Cl,
Br, I, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3,
CN, NO2, NH2 and OH, [0007] or [0008] a group selected from
among [0009] C1-4-alkyl, C1-4-alkyl-O, C2-3-alkenyl,
C2-3-alkynyl, phenyl, phenyl-O, phenyl-C1-3-alkyl- and
phenyl-C1-3-alkyl-O, heteroaryl, heteroaryl-O,
heteroaryl-C1-3-alkyl and heteroaryl-C1-3-alkyl-O, while the
above-mentioned phenyl groups are mono- or disubstituted by R5
groups, [0010] and [0011] R3 denotes hydrogen, [0012] or [0013] a
group selected from among [0014] F, Cl, Br and CH3, [0015]
Rb denotes hydrogen, or an optionally substituted group selected
from among C1-6-alkyl, C3-6-cycloalkyl and
C3-6-cycloalkyl-C1-3-alkyl, [0016] Rc denotes hydrogen, or
an optionally substituted group selected from among C1-6-alkyl,
C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl,
C1-6-alkyl-CO, C3-6-cycloalkyl-CO,
C3-6-cycloalkyl-C1-3-alkyl-CO, C1-6-alkyl-SO2,
C3-6-cycloalkyl-SO2,
C3-6-cycloalkyl-C1-3-alkyl-SO2, phenyl-CO-- and
phenyl-SO2, [0017] Rd denotes hydrogen or [0018] a group
selected from among [0019] F, Cl, Br, I, OH, C1-4-alkyl,
C1-4-alkyl-O, C1-2-alkyl-O substituted by 1 to 3 fluorine
atoms, C3-7-cycloalkyl-O, C3-7-cycloalkyl-C1-4-alkyl-O,
tetrahydrofuran-3-yl-O, tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl-O,
tetrahydrofuranyl-C1-4-alkyl-O and
tetrahydropyranyl-C1-4-alkyl-O, [0020] or [0021]
R4--C1-4-alkyl, wherein the linking of the groups R4 may
take place via each C atom of the alkyl group, [0022] or [0023]
R4--C2-4-alkyl-O, wherein the group R4 is separated from
the oxygen atom by at least 2 C atoms, [0024] or [0025] a group
selected from among [0026] pyrrolidin-2-yl-C1-4-alkyl-O,
pyrrolidin-3-yl-C1-4-alkyl-O, piperidin-2-yl-C1-4-alkyl-O,
piperidin-3-yl-C1-4-alkyl-O, piperidin-4-yl-C1-4-alkyl-O,
azepan-2-yl-C1-4-alkyl-O, azepan-3-yl-C1-4-alkyl-O,
azepan-4-yl-C1-4-alkyl-O, morpholin-2-yl-C1-4-alkyl-O,
morpholin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-pyrrolidin-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-pyrrolidin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-4-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-4-yl-C1-4-alkyl-O,
4-(C1-3-alkyl)-morpholin-2-yl-C1-4-alkyl-O and
4-(C1-3-alkyl)-morpholin-3-yl-C1-4-alkyl-O, [0027] wherein
[0028] R4 denotes a group, which may be identical or different,
selected from among [0029] OH, C1-3-alkyl-O,
C3-6-cycloalkyl-O, NH2, C1-3-alkyl-NH,
(C1-3-alkyl)2N, (2-methoxyethyl)2N, pyrrolidin-1-yl,
piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl,
2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,
8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,
4-(C1-3-alkyl)-piperazin-1-yl, 1,4-diazepan-1-yl,
4-(C1-3-alkyl)-1,4-diazepan-1-yl, HCO--NH, C1-4-alkyl-CO--NH,
C1-3-alkyl-O--C1-3-alkyl-CO--NH, C1-4-alkyl-O--CO--NH,
H2NCONH, C1-3-alkyl-NH--CO--NH, (C1-3-alkyl)2N--CONN,
pyrrolidin-1-yl-CO--NH, piperidin-1-yl-CO--NH, piperazin-1-yl-CO--NH,
4-(C1-3-alkyl)-piperazin-1-yl-CO--NH, morpholin-4-yl-CO--NH and
C1-4-alkyl-SO2--NH, while the pyrrolidinyl, piperidinyl,
azepan-1-yl, piperazinyl, 1,4-diazepan-1-yl, morpholinyl and
1,4-oxazepan-4-yl groups mentioned above in the definition of the group
Rd may each additionally be substituted by one or two
C1-3-alkyl groups, [0030] and wherein the above-mentioned phenyl
groups are mono- or disubstituted by groups R5, wherein [0031]
R5 denotes hydrogen, or [0032] a group, which may be identical or
different, selected from among F, Cl, Br, I, OH, CN, C1-3-alkyl,
C1-3-alkyl-O, CHF2, CF3, --O--CHF2 and --O--CF3,
[0033] and unless stated otherwise, the above-mentioned alkyl groups
may be straight-chain or branched, [0034] A denotes --CO or
--C1-3-alkylene, [0035] wherein the --C1-C3-alkylene
group may be 1-, 2-, 3- or 4-substituted by a group R6, [0036] and
[0037] R6 which may be identical or different, denotes hydrogen, or
[0038] a group selected from among OH, C1-C4-alkyl and
--O--C1-C4-alkyl optionally in the form of the tautomers, the
racemates, the enantiomers, the diastereomers and the mixtures thereof,
and optionally the pharmacologically acceptable acid addition salts
thereof, and the solvates and hydrates thereof.

[0039] Preferred compounds of formula (I) are those wherein [0040]
Ra denotes a group selected from among 3-chloro-2-fluoro-phenyl,
3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl,
2-fluoro-3-methyl-phenyl, 2-fluoro-5-methyl-phenyl,
4-fluoro-3-methyl-phenyl and 3-chloro-2-methyl-phenyl, [0041] Rb and
Rc which may be identical or different, [0042] denote hydrogen or
C1-3-alkyl, [0043] Rd denotes C1-3-alkyl-O, unless
stated otherwise, the above-mentioned alkyl groups may be straight-chain
or branched, [0044] A denotes --CH2CH2, wherein the
--CH2CH2-- group may be substituted by 1 or 2 methyl groups,
optionally in the form of the tautomers, the racemates, the enantiomers,
the diastereomers and the mixtures thereof, and optionally the
pharmacologically acceptable acid addition salts thereof, and the
solvates and hydrates thereof.

[0045] The invention further relates to compounds of formula (I) for use
as medicaments. Preferably the compounds of formula (I) are used in cases
of inflammatory or allergic diseases of the airways.

[0047] It is also particularly preferred to use the compounds of formula
(I) in cases of inflammatory or allergic complaints in which autoimmune
reactions are involved. It is also particularly preferred to use the
compounds of formula (I) in cases of a disease in the form of benign or
malignant tumours.

[0048] The invention further relates to a pharmaceutical formulation
containing a compound of formula (I).

[0050] The invention further relates to medicament combinations which
contain, besides one or more compounds of formula (I), as further active
substances, one or more compounds selected from among the categories of
betamimetics, anticholinergics, corticosteroids, further PDE4-inhibitors,
LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines,
PAF-antagonists and PI3-kinase inhibitors or double or triple
combinations thereof.

[0129] The above-mentioned compounds may also be used as salts within the
scope of the present invention, wherein instead of the methobromide the
salts metho-X are used, wherein X may have the meanings given
hereinbefore for X.sup.-.

[0130] As corticosteroids it is preferable to use compounds selected from
among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide,
deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone,
loteprednol, mometasone, prednisolone, prednisone, rofleponide,
triamcinolone, tipredane and [0131] pregna-1,4-diene-3,20-dione,
6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)
bis(oxy)]-21-[[4-[(nitrooxy)methyl]benzoyl]oxy]-,
(6-alpha,11-beta,16-alpha)-(9CI) (NCX-1024) [0132]
16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-
-3-one (RPR-106541), [0133] (S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate [0134] (S)-(2-oxo-tetrahydro-furan-3S-yl)
6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-
e-17-carbothionate, [0135] cyanomethyl
6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,-
2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxy-
late, optionally in the form of the racemates, enantiomers or
diastereomers thereof and optionally in the form of the salts and
derivatives thereof, the solvates and/or hydrates thereof. Any reference
to steroids includes a reference to any salts or derivatives, hydrates or
solvates thereof which may exist. Examples of possible salts and
derivatives of the steroids may be: alkali metal salts, such as for
example sodium or potassium salts, sulphobenzoates, phosphates,
isonicotinates, acetates, dichloroacetates, propionates, dihydrogen
phosphates, palmitates, pivalates or furoates.

[0265] The PAF antagonists used are preferably compounds selected from
among lexipafant and
4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thien-
o-[3,24]-[1,2,4]triazolo[4,3-a][1,4]diazepine [0266]
6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-
-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,
optionally in the form of the racemates, enantiomers, diastereomers
thereof and optionally in the form of the pharmacologically acceptable
acid addition salts, solvates or hydrates thereof. According to the
invention these acid addition salts are preferably selected from among
the hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

[0267] The dopamine receptor agonists used are preferably compounds
selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine,
lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid
and viozan, optionally in the form of the racemates, enantiomers,
diastereomers thereof and optionally in the form of the pharmacologically
acceptable acid addition salts, solvates or hydrates thereof. According
to the invention these acid addition salts are preferably selected from
among the hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

[0268] Substances of preferred PI3 kinase antagonists that may be used are
preferably compounds selected from among [0269]
5-(Quinoxalin-6-ylmethylene)thiazolidine-2,4-dione (AS-605240), [0270]
2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quina-
zolinone (C-87114), [0271]
2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c-
]quinolin-1-yl]phenyl]propionitrile (BEZ-235), optionally in the form of
the racemates, enantiomers, diastereomers thereof and optionally in the
form of the pharmacologically acceptable acid addition salts, prodrugs,
solvates or hydrates thereof.

Terms and Definitions Used

[0272] By the term "optionally substituted" is meant within the scope of
the invention the above-mentioned group, optionally substituted by a
lower-molecular group. Examples of lower-molecular groups regarded as
chemically meaningful are groups consisting of 1-25 atoms. Preferably
such groups have no negative effect on the pharmacological efficacy of
the compounds. For example the groups may comprise: [0273]
Straight-chain or branched carbon chains, optionally interrupted by
heteroatoms, optionally substituted by rings, heteroatoms or other common
functional groups. [0274] Aromatic or non-aromatic ring systems
consisting of carbon atoms and optionally heteroatoms, which may in turn
be substituted by functional groups. [0275] A number of aromatic or
non-aromatic ring systems consisting of carbon atoms and optionally
heteroatoms which may be linked by one or more carbon chains, optionally
interrupted by heteroatoms, optionally substituted by heteroatoms or
other common functional groups.

[0276] Also included in the subject-matter of this invention are the
compounds according to the invention, including the salts thereof,
wherein one or more hydrogen atoms, for example one, two, three, four or
five hydrogen atoms, are replaced by deuterium.

[0277] Where a hyphen open on one side "-" is used in the structural
formula of a substituent, this hyphen is to be understood as the linkage
point to the remainder of the molecule. The substituent replaces the
corresponding groups Ra, Rb, etc. If no hyphen open on one side
is used in the structural formula of a substituent, the linkage point to
the remainder of the molecule is clear from the structural formula
itself.

[0278] Compounds of general formula (I) may contain acid groups, primarily
carboxyl groups, and/or basic groups such as e.g. amino functions.
Compounds of general formula (I) may therefore be present as internal
salts, as salts with pharmaceutically useable inorganic acids such as
hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or
organic acids (such as for example maleic acid, fumaric acid, citric
acid, tartaric acid or acetic acid) or as salts with pharmaceutically
useable bases such as alkali metal or alkaline earth metal hydroxides or
carbonates, zinc or ammonium hydroxides or organic amines such as e.g.
diethylamine, triethylamine, triethanolamine, inter alia. For preparing
the alkali metal and alkaline earth metal salts of the compound of
formula (I), it is preferable to use the alkali metal and alkaline earth
metal hydroxides and hydrides, while the hydroxides and hydrides of the
alkali metals, particularly sodium and potassium are preferred, and
sodium and potassium hydroxide are particularly preferred. (See also
Pharmaceutical Salts, S. M. Birge et al., J. Pharm. Sci. (1977), 66,
1-19)

[0279] As already mentioned, the compounds of general formula (I) may be
converted into the salts thereof, particularly for pharmaceutical use,
into the pharmacologically acceptable acid addition salts thereof with an
inorganic or organic acid. Suitable acids for this purpose include for
example succinic acid, hydrobromic acid, acetic acid, fumaric acid,
maleic acid, methanesulphonic acid, lactic acid, phosphoric acid,
hydrochloric acid, sulphuric acid, tartaric acid or citric acid. In
addition, mixtures of the above-mentioned acids may be used.

[0280] The present invention relates to the respective compounds,
optionally in the form of the individual diastereomers, mixtures of the
individual diastereomers and/or individual enantiomers, mixtures of the
individual enantiomers or racemates thereof, in the form of the tautomers
as well as in the form of the free bases or the corresponding acid
addition salts with pharmacologically acceptable acids--such as for
example acid addition salts with hydrohalic acids--for example
hydrochloric or hydrobromic acid or organic acids--such as for example
tartaric acid, fumaric acid, citric acid or methanesulphonic acid.

[0281] "Protective groups" for the purposes of the present invention is a
collective term for organic groups with which certain functional groups
of a molecule containing a number of active centres can temporarily be
protected from attack by reagents so that reactions take place only at
the desired (unprotected) sites. The protective groups should be
introduced selectively under mild conditions. They must be stable for the
duration of the protection under all the conditions of the reactions and
purifying procedures which are to be carried out; racemisations and
epimerisations must be suppressed. Protective groups should be capable of
being cleaved again under mild conditions selectively and ideally in high
yields. The choice of a suitable protective group, the reaction
conditions (solvent, temperature, duration, etc.), and also the options
for removing a protective group are known in the art (e.g. Philip
Kocienski, Protecting Groups, 3rd ed. 2004, THIEME, Stuttgart, ISBN:
3131370033).

[0294] The term diastereomerically pure describes within the scope of the
present invention compounds of formula (I), which are present in a
diastereomeric purity of at least 85% de, preferably at least 90% de,
particularly preferably >95% de. The term de (diastereomeric excess)
is known in the art and describes the optical purity of diastereomeric
compounds.

[0295] The term enantiomerically pure describes within the scope of the
present invention compounds of formula (I), which are present in an
enantiomerical purity of at least 85% ee, preferably at least 90% ee,
particularly preferably >95% ee. The term ee (enantiomeric excess) is
known in the art and describes the optical purity of chiral compounds.

[0296] By the term "C1-6-alkyl" (including those which are part of
other groups) are meant branched and unbranched alkyl groups with 1 to 6
carbon atoms and by the term "C1-4-alkyl" are meant branched and
unbranched alkyl groups with 1 to 4 carbon atoms. Preferred are alkyl
groups with 1 to 4 carbon atoms, particularly preferably alkyl groups
with 1 to 2 carbon atoms. Examples include: methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr,
n-Bu, i-Bu, t-Bu, etc. may optionally also be used for the
above-mentioned groups. Unless stated otherwise, the definitions propyl,
butyl, pentyl and hexyl include all the possible isomeric forms of the
groups in question. Thus, for example, propyl includes n-propyl and
iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

[0297] By the term "C1-3-alkylene" (including those which are part of
other groups) are meant branched and unbranched alkylene groups with 1 to
3 carbon atoms. Preferred are alkylene groups with 1 to 2 carbon atoms.
Examples include: methylene, ethylene, propylene and 1-methylethylene.
Unless stated otherwise, the definition propylene includes all the
possible isomeric forms of the groups in question with the same number of
carbons. Thus, for example, propylene also includes 1-methylethylene.

[0298] By the term "C2-3-alkenyl" (including those which are part of
other groups) are meant alkenyl groups with 2 to 3 carbon atoms, if they
have at least one double bond. Examples include: ethenyl or vinyl. Unless
stated otherwise, the definition "C2-3-alkenyl" includes all the
possible isomeric forms of the groups in question with the same number of
carbons. Thus, for example, propenyl includes 1-propen-1-yl,
1-propen-2-yl and 2-propen-1-yl.

[0299] By the term "C2-3-alkynyl" (including those which are part of
other groups) are meant alkynyl groups with 2 to 3 carbon atoms, if they
have at least one triple bond. Examples include: ethynyl or propynyl.
Unless stated otherwise, the definition "C2-3-alkynyl" includes all
the possible isomeric forms of the groups in question with the same
number of carbons. Thus, for example, propynyl includes propyn-1-yl and
2-propyn-1-yl.

[0300] By the term "C3-7-cycloalkyl" (including those which are part
of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms.
Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be
substituted by one or more groups selected from among methyl, ethyl,
iso-propyl, tert-butyl, hydroxy and fluorine.

[0301] By the term "aryl" (including those which are part of other groups)
are meant aromatic ring systems with 6, 10 or 14 carbon atoms. Examples
include: phenyl, naphthyl, anthracenyl or phenanthrenyl, the preferred
aryl group being phenyl. Unless otherwise stated, the aromatic groups may
be substituted by one or more groups R5. Particularly preferably the
term "aryl" in each case denotes a phenyl group which is mono- or
disubstituted by R5, wherein the substituents R5 may be
identical or different and [0302] R5 denotes hydrogen, or [0303]
a group, which may be identical or different, selected from among F, Cl,
Br, I, OH, CN, C1-3-alkyl, C1-3-alkyl-O, CHF2, CF3,
--O--CHF2 and --O--CF3.

[0304] By the term "heteroaryl" are meant 5-10-membered mono- or bicyclic
heteroaryl rings, wherein up to three C atoms may be replaced by one or
more heteroatoms selected from among oxygen, nitrogen or sulphur, these
rings containing sufficient conjugated double bonds to form an aromatic
system. Each of the above-mentioned heterocycles may optionally also be
fused to a benzene ring. The heteroaryl rings may, unless otherwise
described, carry one or more substituents, for example. The ring may be
linked to the molecule via a carbon atom or, if available, via a nitrogen
atom. The following are examples of five- or six-membered heterocyclic
aromatic groups:

[0306] Particularly preferably, the term "heteroaryl" denotes a pyridinyl,
pyridazinyl, pyrimidinyl or pyrazinyl group, which is mono- or
disubstituted in each case by the group R5, wherein the substituents
R5 may be identical or different and R5 is as hereinbefore
defined.

[0307] "Halogen" within the scope of the present invention denotes
fluorine, chlorine, bromine or iodine. Unless stated to the contrary,
fluorine, chlorine and bromine are regarded as preferred halogens.

[0308] The substituent Ra may represent a phenyl or 1-phenylethyl
group, preferably a phenyl group, wherein the phenyl nucleus is
substituted in each case by the groups R1 to R3.

[0310] The substituent Rb may represent hydrogen, or an optionally
substituted group selected from among C1-6-alkyl,
C3-6-cycloalkyl- and C3-6-cycloalkyl-C1-3-alkyl,
preferably hydrogen and C1-3-alkyl, particularly preferably hydrogen
and methyl.

[0311] The substituent Rc may represent hydrogen, or an optionally
substituted group selected from among C1-6-alkyl,
C3-6-cycloalkyl- and C3-6-cycloalkyl-C1-3-alkyl,
C1-6-alkyl-CO, C3-6-cycloalkyl-CO-- and
C3-6-cycloalkyl-C1-3-alkyl-CO, C1-6-alkyl-SO2,
C3-6-cycloalkyl-SO2-- and
C3-6-cycloalkyl-C1-3-alkyl-SO2, phenyl-CO-- and
phenyl-SO2, preferably hydrogen and C1-3-alkyl, particularly
preferably hydrogen and methyl.

[0312] The substituent Rd may denote hydrogen or [0313] a group
selected from among [0314] F, Cl, Br, I, OH, C1-4-alkyl,
C1-4-alkyl-O, C1-2-alkyl-O substituted by 1 to 3 fluorine
atoms, C3-7-cycloalkyl-O, C3-7-cycloalkyl-C1-4-alkyl-O,
tetrahydrofuran-3-yl-O, tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl-0,
tetrahydrofuranyl-C1-4-alkyl-O-- and
tetrahydropyranyl-C1-4-alkyl-O, or [0315] R4--C1-4-alkyl,
wherein the linking of the groups R4 may take place via each C atom
of the alkyl group, or [0316] R4--C2-4-alkyl-O, wherein the
group R4 is separated from the oxygen atom by at least 2 C atoms, or
[0317] a group selected from among [0318]
pyrrolidin-2-yl-C1-4-alkyl-O, pyrrolidin-3-yl-C1-4-alkyl-O,
piperidin-2-yl-C1-4-alkyl-O, piperidin-3-yl-C1-4-alkyl-O,
piperidin-4-yl-C1-4-alkyl-O, azepan-2-yl-C1-4-alkyl-O,
azepan-3-yl-C1-4-alkyl-O, azepan-4-yl-C1-4-alkyl-O,
morpholin-2-yl-C1-4-alkyl-O, morpholin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-pyrrolidin-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-pyrrolidin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-piperidin-4-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-2-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-3-yl-C1-4-alkyl-O,
1-(C1-3-alkyl)-azepan-4-yl-C1-4-alkyl-O,
4-(C1-3-alkyl)-morpholin-2-yl-C1-4-alkyl-O and
4-(C1-3-alkyl)-morpholin-3-yl-C1-4-alkyl-O--, preferably
C1-3-alkyl-O--, particularly preferably CH3--O--, wherein the
pyrrolidinyl, piperidinyl, azepan-1-yl, piperazinyl, 1,4-diazepan-1-yl,
morpholinyl and 1,4-oxazepan-4-yl groups mentioned above in the
definition of the group Rd may each additionally be substituted by
one or two C1-3-alkyl groups, and wherein the above-mentioned phenyl
groups are mono- or disubstituted by groups R5.

[0335] The substituent R5 may represent hydrogen, or [0336] a
group, which may be identical or different, selected from among [0337] F,
Cl, Br, I, OH, CN, C1-3-alkyl, C1-3-alkyl-O, CHF2,
CF3, --O--CHF2 and --O--CF3.

[0338] A may denote --CO or --C1-C3-alkylene, preferably
--CH2CH2, [0339] wherein the --C1-C3-alkylene group
may be 1-, 2-, 3- or 4-, preferably 1- or 2-substituted by a group
R6,

[0340] The substituent R6, which may be identical or different, may
represent hydrogen, or a group selected from among OH,
C1-C4-alkyl and --O--C1-C4-alkyl, preferably methyl.
A particularly preferred definition of A is --CH2CH2--.

Methods of Preparation

[0341] The following methods are suitable, for example, for preparing
compounds of general formula (I):

a) reacting a compound of general formula

##STR00005##

wherein Ra and Rd are as hereinbefore defined, with a compound
of general formula

##STR00006##

wherein Rb, Rc and A are as hereinbefore defined and Z1
denotes a leaving group such as a halogen atom, e.g. a chlorine or
bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or
p-toluenesulphonyloxy group or a hydroxy group.

[0342] With a compound of general formula (III), wherein Z1 denotes a
halogen atom or a sulphonyloxy group, the reaction is expediently carried
out in a solvent such as ethanol, isopropanol, acetonitrile, toluene,
tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or
N-methylpyrrolidinone, preferably in the presence of a base such as
potassium carbonate, potassium-tert-butoxide, sodium hydride or
N-ethyl-diisopropylamine, at temperatures in the range from 20° C.
to 160° C., for example at temperatures in the range from
60° C. to 140° C.

[0343] With a compound of general formula III wherein Z1 denotes a
hydroxy group, the reaction is carried out in the presence of a
dehydrating agent, preferably in the presence of a phosphine and an
azodicarboxylic acid derivative such as e.g. triphenylphosphine/diethyl
azodicarboxylate, conveniently in a solvent such as methylene chloride,
acetonitrile, tetrahydrofuran, dioxane, toluene or ethyleneglycol
diethylether at temperatures between -50 and 150° C., but
preferably at temperatures between -20 and 80° C.

[0344] b) In order to prepare compounds of general formula I wherein
Rb and Rc each denote a hydrogen atom and A represents a --CO--
group, reacting a compound of general formula

##STR00007##

wherein Ra and Rd are as hereinbefore defined, with an alkali
metal cyanide and ammonium carbonate.

[0345] The reaction is carried out for example in a solvent or mixture of
solvents such as methanol, ethanol, ethanol/water or isopropanol at
temperatures between ambient temperature and 120° C. Further
references to the synthesis of hydantoins can be found for example in the
following publication:

wherein Rb, Rc, Rd and A are as hereinbefore defined, with
a halogenating agent, for example an acid halide such as thionyl
chloride, thionyl bromide, phosphorus trichloride, phosphorus
pentachloride, phosphorus oxychloride, or triphenylphosphine/carbon
tetrachloride or triphenylphosphine/N-chlorosuccinimide to obtain an
intermediate compound of general formula (VI),

##STR00009##

wherein Rb, Rc, Rd and A are as hereinbefore defined and
Z2 denotes a halogen atom such as a chlorine or bromine atom, and
subsequent reaction with a compound of general formula (VII),

Ra--NH2 (VII),

wherein Ra is as hereinbefore defined, or the salts thereof.

[0347] The reaction with the halogenating agent is optionally carried out
in a solvent such as methylene chloride, chloroform, acetonitrile or
toluene and optionally in the presence of a base such as
N,N-diethylaniline, triethylamine or N-ethyl-diisopropylamine at
temperatures in the range from 20° C. to 160° C.,
preferably from 40° C. to 120° C. Preferably, however, the
reaction is carried out with thionyl chloride and catalytic amounts of
dimethylformamide at the boiling temperature of the reaction mixture or
with phosphorus oxychloride in acetonitrile in the presence of
triethylamine at the boiling temperature of the reaction mixture or with
triphenylphosphine/carbon tetrachloride or with
triphenylphosphine/N-chlorosuccinimide in acetonitrile.

[0348] The reaction of the compound of general formula (VI) with the
compound of general formula (VII) or the salts thereof is conveniently
carried out in a solvent such as ethanol, isopropanol, acetonitrile,
dioxane or dimethylformamide, optionally in the presence of a base such
as potassium carbonate, triethylamine or N-ethyl-diisopropylamine, at
temperatures in the range from 20° C. and 160° C.,
preferably from 60° C. to 120° C. However, the reaction is
preferably carried out in isopropanol at the boiling temperature of the
reaction mixture.

[0349] The reaction of a compound of general formula (V) to obtain a
compound of general formula (I) may also be carried out as a one-pot
reaction, for example in acetonitrile in the presence of triethylamine.

d) In order to prepare compounds of general formula I wherein Rd
denotes one of the optionally substituted alkyloxy groups mentioned
hereinbefore: reacting a compound of general formula

##STR00010##

wherein Ra, Rb, Rc and A are as hereinbefore defined, with
a compound of general formula

Z3-Rd', (IX)

wherein Rd' denotes a group selected from among C1-4-alkyl,
C1-2-alkyl substituted by 1 to 3 fluorine atoms,
C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl,
tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydro-pyran-4-yl,
tetrahydrofuranyl-C1-4-alkyl and tetrahydropyranyl-C1-4-alkyl,
or [0350] R4--C2-4-alkyl, wherein the group R4 is
separated from Z3 by at least 2 C atoms, or [0351] a group selected
from among [0352] pyrrolidin-2-yl-C1-4-alkyl,
pyrrolidin-3-yl-C1-4-alkyl, piperidin-2-yl-C1-4-alkyl,
piperidin-3-yl-C1-4-alkyl, piperidin-4-yl-C1-4-alkyl,
azepan-2-yl-C1-4-alkyl, azepan-3-yl-C1-4-alkyl,
azepan-4-yl-C1-4-alkyl, morpholin-2-yl-C1-4-alkyl,
morpholin-3-yl-C1-4-alkyl,
1-(C1-3-alkyl)-pyrrolidin-2-yl-C1-4-alkyl,
1-(C1-3-alkyl)-pyrrolidin-3-yl-C1-4-alkyl,
1-(C1-3-alkyl)-piperidin-2-yl-C1-4-alkyl,
1-(C1-3-alkyl)-piperidin-3-yl-C1-4-alkyl,
1-(C1-3-alkyl)-piperidin-4-yl-C1-4-alkyl,
1-(C1-3-alkyl)-azepan-2-yl-C1-4-alkyl,
1-(C1-3-alkyl)-azepan-3-yl-C1-4-alkyl,
1-(C1-3-alkyl)-azepan-4-yl-C1-4-alkyl,
4-(C1-3-alkyl)-morpholin-2-yl-C1-4-alkyl,
4-(C1-3-alkyl)-morpholin-3-yl-C1-4-alkyl, and Z3 denotes a
leaving group such as a halogen atom, an alkylsulphonyloxy,
arylsulphonyloxy or a hydroxy group.

[0353] If the leaving group is a halogen atom such as a chlorine, bromine
or iodine atom or an alkylsulphonyloxy or arylsulphonyloxy group such as
the methanesulphonyloxy or p-toluenesulphonyloxy group, the reaction is
preferably carried out in the presence of an organic or inorganic base
such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine.
If the leaving group is a hydroxy group, the reaction is carried out in
the presence of a dehydrating agent, preferably in the presence of a
phosphine and an azodicarboxylic acid derivative such as e.g.
triphenylphosphine/diethyl azodicarboxylate.

e) In order to prepare compounds of general formula I wherein Rd denotes
a R4'--C2-4-alkyl-O-- group, wherein the group R4' is
separated from the oxygen atom by at least 2 C atoms, and R4'
denotes a group selected from among NH2, C1-3-alkyl-NH,
(C1-3-alkyl)2N, (2-methoxyethyl)2N, pyrrolidin-1-yl,
piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl,
2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,
8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,
4-(C1-3-alkyl)piperazin-1-yl, 1,4-diazepan-1-yl,
4-(C1-3-alkyl)-1,4-diazepan-1-yl: reacting a compound of general
formula

##STR00011##

wherein Ra, Rb, Rc and A are as hereinbefore defined and
Z4 denotes a leaving group such as a halogen atom, e.g. a chlorine
or bromine atom or a sulphonyloxy group such as a methanesulphonyloxy or
p-toluenesulphonyloxy group, with

H--R4', (XI)

wherein R4' is as hereinbefore defined. f) In order to prepare
compounds of general formula I wherein Rb denotes a hydrogen atom:
cleaving a protective group from a compound of general formula

##STR00012##

wherein Ra, Rc, Rd and A are as hereinbefore defined and
Rb', denotes a protective group, for example an optionally
substituted benzyl group, a tert.-butyl group or a
2-(trimethylsilyl)ethyl group.

[0354] An optionally substituted benzyl group is for example cleaved
hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such
as palladium/charcoal in a suitable solvent such as methanol, ethanol,
ethyl acetate or glacial acetic acid, optionally with the addition of an
acid such as hydrochloric acid, at temperatures between 0 and 100°
C., but preferably at ambient temperatures between 20 and 60° C.,
and under a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5
bar. However, a 2,4-dimethoxybenzyl group is preferably cleaved in
trifluoroacetic acid in the presence of anisol, thioanisol,
pentamethylbenzene or triethylsilane.

[0355] An optionally substituted benzyl group or a tert.-butyl group may
for example also be cleaved by treating with an acid such as
trifluoroacetic acid, hydrochloric acid or hydrobromic acid, optionally
using a solvent such as methylene chloride or toluene, optionally in the
presence of anisole, thioanisole, pentamethylbenzene or triethylsilane.

[0356] A 2-(trimethylsilyl)ethyl group is cleaved for example by treatment
with fluorides such as tetrabutylammonium fluoride, optionally using a
solvent such as tetrahydrofuran or dioxane.

[0357] Other suitable protective groups and possible ways of introducing
and cleaving them are described for example in "Protective Groups in
Organic Synthesis" by Theodora W. Greene and Peter G. M. Wuts, Wiley-VCH,
or Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME.

g) In order to prepare compounds of general formula I wherein Rc
denotes a hydrogen atom: cleaving a protective group from a compound of
general formula

##STR00013##

wherein Ra, Rb, Rd and A are as hereinbefore defined and
Rc' denotes a protective group, for example an optionally
substituted benzyl group or a formyl, acetyl, trifluoroacetyl,
methoxycarbonyl, ethoxycarbonyl, tert.-butoxycarbonyl or
benzyloxycarbonyl group.

[0358] The protective group is cleaved, for example, hydrolytically in an
aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,
tetrahydrofuran/water or dioxane/water, in the presence of an acid such
as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the
presence of an alkali metal base such as sodium hydroxide or potassium
hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at
temperatures between 0 and 120° C., preferably at temperatures
between 10 and 100° C.

[0359] An optionally substituted benzyl group, or a
benzyloxycarbonylbenzyl group is cleaved, for example,
hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such
as palladium/charcoal in a suitable solvent such as methanol, ethanol,
ethyl acetate or glacial acetic acid, optionally with the addition of an
acid such as hydrochloric acid at temperatures between 0 and 100°
C., but preferably at ambient temperatures between 20 and 60° C.,
and under a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5
bar.

[0360] A tert.-butyloxycarbonyl group is preferably cleaved by treatment
with an acid such as trifluoroacetic acid or hydrochloric acid,
optionally using a solvent such as methylene chloride, dioxane, methanol
or diethyl ether.

[0361] A trifluoroacetyl group is preferably cleaved by treatment with an
acid such as hydrochloric acid, optionally in the presence of a solvent
such as acetic acid at temperatures between 50 and 120° C. or by
treatment with sodium hydroxide solution, optionally in the presence of a
solvent such as tetrahydrofuran at temperatures between 0 and 50°
C.

[0362] Other suitable protective groups and possible ways of introducing
and cleaving them are described for example in "Protective Groups in
Organic Synthesis" by Theodora W. Greene and Peter G. M. Wuts, Wiley-VCH,
or Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME.

h) In order to prepare compounds of general formula I wherein A denotes a
--C2-C3-alkylene group: cyclising a compound of general formula

##STR00014##

wherein Ra, Rb, Rc and Rd are as hereinbefore
defined, A' denotes a --C2-C3-alkylene group and Z5
denotes a leaving group such as a halogen atom, a hydroxy or alkyloxy
group.

[0363] If the leaving group is a hydroxy group, the reaction is carried
out in the presence of a dehydrating agent such as
N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide,
0-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluronium-tetrafluoroborate
(TBTU) or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexaflu-
orophosphate (HATU), conveniently in a solvent such as methylene chloride,
N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dioxane or
ethyleneglycol diethyl ether at temperatures between -50° C. and
100° C., but preferably at temperatures between -20° C. and
60° C.

[0364] If the leaving group is a halogen atom, the reaction is preferably
carried out in the presence of a base such as triethylamine or
N-ethyl-diisopropylamine, conveniently in a solvent such as methylene
chloride, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dioxane
or ethyleneglycol diethyl ether at temperatures between -50° C.
and 100° C., but preferably at temperatures between -20° C.
and 60° C.

[0365] If the leaving group is an alkyloxy group, the reaction is
optionally carried out in the presence of a base such as potassium
carbonate, sodium hydroxide, triethylamine or N-ethyl-diisopropylamine,
conveniently in a solvent such as methanol, ethanol, isopropanol,
methylene chloride, N,N-dimethylformamide, acetonitrile, tetrahydrofuran,
dioxane or ethyleneglycol diethyl ether at temperatures between
-50° C. and 120° C., but preferably at temperatures between
0° C. and 80° C.

[0366] If according to the invention a compound of general formula I is
obtained which contains an amino, alkylamino or imino group, this may be
converted by acylation or sulphonylation into a corresponding acyl or
sulphonyl compound of general formula I, wherein the acylating agents
used may be for example carboxylic acid halides, carboxylic acid
anhydrides and carboxylic acids with activating agents such as
N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide or
O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluronium-tetrafluoroborate and
sulphonyl halides as sulphonylating agents, and/or

[0367] if a compound of general formula I is obtained which contains an
amino, alkylamino or imino group, it may be converted by alkylation or
reductive alkylation into a corresponding alkyl compound of general
formula I and/or

[0368] if a compound of general formula I is obtained which contains an
alkoxycarbonyl group, it may be converted by ester cleaving into a
carboxylic acid, and/or

[0369] if a compound of general formula I is obtained which contains an
alkoxycarbonyl group, it may be converted by reaction with an amine into
a carboxylic acid amide derivative and/or

[0370] if a compound of general formula I is obtained which contains a
carboxy group, it may be converted by reaction with an amine into a
carboxylic acid amide derivative.

[0371] In the reactions described hereinbefore any reactive groups present
such as hydroxy, amino, alkylamino or imino groups may be protected
during the reaction by conventional protective groups which are cleaved
again after the reaction.

[0372] For example a protecting group for a hydroxy group might be the
trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

[0374] Any protective group used is optionally subsequently cleaved for
example by hydrolysis in an aqueous solvent, e.g. in water,
isopropanol/water, acetic acid/water, tetrahydrofuran/water or
dioxane/water, in the presence of an acid such as trifluoroacetic acid,
hydrochloric acid or sulphuric acid or in the presence of an alkali metal
base such as sodium hydroxide or potassium hydroxide or aprotically, e.g.
in the presence of iodotrimethylsilane, at temperatures between 0 and
120° C., preferably at temperatures between 10 and 100° C.

[0375] A benzyl, methoxybenzyl or benzyloxycarbonyl group, however, is
cleaved by hydrogenolysis, for example, e.g. with hydrogen in the
presence of a catalyst such as palladium/charcoal in a suitable solvent
such as methanol, ethanol, ethyl acetate or glacial acetic acid,
optionally with the addition of an acid such as hydrochloric acid at
temperatures between 0 and 100° C., but preferably at ambient
temperatures between 20 and 60° C., and under a hydrogen pressure
of 1 to 7 bar, but preferably from 3 to 5 bar. A 2,4-dimethoxybenzyl
group, however, is preferably cleaved in trifluoroacetic acid in the
presence of anisole, thioanisole, pentamethylbenzene or triethylsilane.

[0376] A tert.-butyl or tert.-butyloxycarbonyl group is preferably cleaved
by treatment with an acid such as trifluoroacetic acid or hydrochloric
acid or by treating with iodotrimethylsilane, optionally using a solvent
such as methylene chloride, dioxane, methanol or diethyl ether.

[0377] A trifluoroacetyl group is preferably cleaved by treatment with an
acid such as hydrochloric acid, optionally in the presence of a solvent
such as acetic acid at temperatures between 50 and 120° C. or by
treatment with sodium hydroxide solution, optionally in the presence of a
solvent such as tetrahydrofuran at temperatures between 0 and 50°
C.

[0378] Other suitable protective groups and possible ways of introducing
and cleaving them are described for example in "Protective Groups in
Organic Synthesis" by Theodora W. Greene and Peter G. M. Wuts, Wiley-VCH,
or Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME.

[0379] Moreover, the compounds of general formula I obtained may be
resolved into their enantiomers and/or diastereomers, as mentioned
hereinbefore. Thus, for example, cis/trans mixtures may be resolved into
their cis and trans isomers, and compounds with at least one optically
active carbon atom may be separated into their enantiomers.

[0380] Thus, for example, the cis/trans mixtures obtained may be resolved
by chromatography into the cis and trans isomers thereof, the compounds
of general formula I obtained which occur as racemates may be separated
by methods known per se (cf. Allinger N. L. and Eliel E. L. In "Topics in
Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical
antipodes and compounds of general formula I with at least 2 asymmetric
carbon atoms may be resolved into their diastereomers on the basis of
their physical-chemical differences using methods known per se, e.g. by
chromatography and/or fractional crystallisation, and, if these compounds
are obtained in racemic form, they may subsequently be resolved into the
enantiomers as mentioned above.

[0381] The enantiomers are preferably separated by column separation on
chiral phases or by recrystallisation from an optically active solvent or
by reacting with an optically active substance which forms salts or
derivatives such as e.g. esters or amides with the racemic compound,
particularly acids and the activated derivatives or alcohols thereof, and
separating the diastereomeric mixture of salts or derivatives thus
obtained, e.g. on the basis of their differences in solubility, whilst
the free antipodes may be released from the pure diastereomeric salts or
derivatives by the action of suitable agents. Optically active acids in
common use are e.g. the D- and L-forms of tartaric acid or
dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic
acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid.
An optically active alcohol may be for example (+) or (-)-menthol and an
optically active acyl group in amides, for example, may be a (+)- or
(-)-menthyloxycarbonyl.

[0383] The compounds of general formulae II to XXIII used as starting
materials are known from the literature to some extent or may be obtained
by methods known from the literature (cf. Examples I to V), optionally
with the additional introduction of protecting groups.

[0384] Standard processes for preparing the starting materials are
described for example in "March's Advanced Organic Chemistry" by Michael
B. Smith and Jerry March, Wiley-VCH or in "Science of
Synthesis/Houben-Weyl" published by Thieme.

[0385] One possible method of obtaining compounds of general formula (V)
and (VI) is as follows:

##STR00015##

[0386] Starting from a compound of general formula (XV), wherein PG
denotes a protective group such as for example benzyl, 4-methoxybenzyl or
2,4-dimethoxybenzyl, the reaction is carried out with a compound of
general formula (III) analogously to the previously described process a)
to obtain a compound of general formula (XVI). The compounds of general
formula (XV) are known from the literature (cf. E.g. WO 2004/108664 or WO
2007/003486) or may be obtained by methods known from the literature.

[0387] The cleaving of the protective group from a compound of general
formula (XVI) to obtain a compound of general formula (V) is carried out,
if PG denotes benzyl, with hydrogen, for example, in the presence of a
catalyst such as palladium/charcoal. The cleaving of the protective group
if PG denotes 4-methoxybenzyl or 2,4-dimethoxybenzyl may also be carried
out oxidatively (e.g. with cerium (IV)-ammonium nitrate or with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone) or with acids (e.g. with
trifluoroacetic acid in the presence of anisole, thioanisole,
pentamethylbenzene or triethylsi lane).

[0388] A compound of general formula (V) may then be converted into a
compound of general formula (VI), as described in the previous process
c). The meanings for Rb, Rc, Rd, A, Z1 and Z2 in
the compounds of Scheme 1 are defined as mentioned hereinbefore.

[0389] Another possible way of obtaining compounds of general formula
(XVI) is as follows:

##STR00016##

[0390] Starting from a compound of general formula (XV), wherein PG
denotes a protective group such as for example benzyl, 4-methoxybenzyl or
2,4-dimethoxybenzyl, the reaction is carried out with a compound of
general formula (XVII) analogously to the previously described process a)
to form a compound of general formula (XVIII). After cleaving of the
ketal to form the ketone, the reaction is carried out to obtain a
compound of general formula (XX) (analogously to e.g. WO 2008/079735).
After reduction of the double bond (analogously to e.g. WO 2008/079735)
the protective group PG' is cleaved to form a compound of general formula
(XXII). The other steps leading to a compound of general formula (XVI)
are carried out for example analogously to Examples III, II, I, and 1.
The meanings of Rb, Rc, Rd, A and Z1 in the compounds
of Scheme 2 are defined as hereinbefore. PG' denotes a protective group,
for example formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,
tert.-butoxycarbonyl or benzyloxycarbonyl and R' denotes a
C1-4-alkyl group, for example methyl or ethyl.

[0391] Another possible way of obtaining compounds of general formula
(XXI) is as follows:

##STR00017##

[0392] Starting from a compound of general formula (XV), wherein PG
denotes a protective group such as for example benzyl, 4-methoxybenzyl or
2,4-dimethoxybenzyl, the reaction is carried out with a compound of
general formula (XXIII) analogously to the previously described process
a) to form a compound of general formula (XXI). The meanings of Rd,
PG, PG', R' and Z1 in the compounds of Scheme 3 are as hereinbefore
defined.

[0393] As already mentioned hereinbefore, the compounds of general formula
(I) according to the invention and the physiologically acceptable salts
thereof have valuable pharmacological properties, particularly an
inhibiting effect on signal transduction mediated by the Epidermal Growth
Factor receptor (EGF-R), whilst this may be achieved for example by
inhibiting ligand bonding, receptor dimerisation or tyrosine kinase
itself. It is also possible to block the transmission of signals to
components located further downstream.

[0394] The following Examples are intended to illustrate the present
invention without restricting it:

[0396] A mixture of 970 mg methyl
cis/trans-(S)-[(2-tert.-butoxycarbonylamino-ethyl)-methyl-amino]-{4-[4-(3-
-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexyl}-ac-
etate, 2 ml trifluoroacetic acid and 8 ml methylene chloride is stirred
overnight at ambient temperature. Then the reaction mixture is evaporated
down in vacuo, leaving a brownish solid, which is reacted further without
any further purification.

[0425] 490 mg tert. Butyl (2-oxo-ethyl)-carbamate followed by 180 μl
glacial acetic acid and 150 mg sodium triacetoxyborohydride are added to
1.50 g methyl
cis/trans-(S)-amino-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quina-
zolin-6-yloxy]-cyclohexyl}-acetate in 40 ml of tetrahydrofuran. The
reaction mixture is stirred overnight at ambient temperature, then
another 70 mg tert. Butyl (2-oxo-ethyl)-carbamate and 150 mg sodium
triacetoxyborohydride are added and the mixture is stirred for a further
four hours at ambient temperature. For working up the reaction mixture is
diluted with 20 ml of ethyl acetate, combined with 10 ml 10% potassium
carbonate solution and stirred thoroughly. The aqueous phase is separated
off and extracted with ethyl acetate. The combined organic phases are
washed with saturated sodium chloride solution, dried on magnesium
sulphate and evaporated down. The crude product is reacted further
without any further purification.

[0426] Mass spectrum (ESI.sup.+): m/z=632, 634 [M+H].sup.+

[0427] The following compounds are obtained analogously to Example III:

[0437] After a further four hours at 80° C. the reaction mixture is
cooled and diluted with ethyl acetate and water. The aqueous phase is
separated off and extracted with ethyl acetate. The combined organic
phases are dried on magnesium sulphate and evaporated down. The crude
product is purified by chromatography through a silica gel column with
methylene chloride/methanol/conc. Ammonia (99/1/0.1 auf 8/2/0.1) as
eluant.

[0438] Yield: 5.90 g (32% of theory)

[0439] Mass spectrum (ESI.sup.+): m/z=589, 591 [M+H].sup.+

[0440] The following compounds are obtained analogously to Example IV:

[0447] For working up 50 ml saturated sodium hydrogen carbonate solution
are added. The aqueous phase is separated off and extracted with
methylene chloride. The combined organic phases are washed with saturated
sodium chloride solution, dried on magnesium sulphate and evaporated
down. A viscous oil remains which is further reacted without any further
purification.

[0458] A mixture of 700 mg methyl
[(2-amino-ethyl)-methyl-amino]-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-me-
thoxy-quinazolin-6-yloxy]-cyclohexyl}-acetate, 7 ml of methanol and 0.65
ml 4N sodium hydroxide solution is stirred for three hours at ambient
temperature. Then the reaction mixture is evaporated down and extracted
with ethyl acetate. The organic phase is dried on magnesium sulphate and
evaporated down. The flask residue is purified by chromatography through
a silica gel column with methylene chloride/methanol/conc. ammonia
(98/2/0.1 auf 8/2/0.1) as eluant. The crude product is stirred with
diisopropylether, suction filtered and dried.

[0479] The cyclisation is carried out in methanol in the presence of
triethylamine at ambient temperature.

[0480] Mass spectrum (ESI.sup.+): m/z=500, 502 [M+H].sup.+

Biological Test

[0481] The biological properties of the new compounds are investigated as
follows, for example:

[0482] The inhibition of the EGF-R-mediated signal transmission can be
demonstrated e.g. with cells which express human EGF-R and whose survival
and proliferation depend on stimulation by EGF or TGF-alpha. A murine
haematopoietic cell line is genetically modified so as to express
functional human EGF-R. The proliferation of this cell line can therefore
be stimulated by EGF.

[0483] The test is carried out as follows:

[0484] The cells are cultivated in RPMI/1640 medium. The proliferation is
stimulated with 20 ng/ml of human EGF (Promega). To investigate the
inhibitory activity of the compounds according to the invention these
compounds are dissolved in 100% dimethylsulphoxide (DMSO) and added to
the cultures in various dilutions, the maximum DMSO concentration being
1%. The cultures are incubated for 48 hours at 37° C.

[0485] In order to determine the inhibitory activity of the compounds
according to the invention the relative cell number is measured in O.D.
Units using the Cell Titer 96® AQueous Non-Radioactive Cell
Proliferation Assay (Promega). The relative cell number is calculated as
a percentage of the control and the concentration of active substance
which inhibits the proliferation of the cells by 50% (IC50) is derived
therefrom.

[0486] The compounds of general formula (I) according to the invention
exhibit IC50 values of <10 micromolar, preferably <1 micromolar,
for example.

[0487] As has been found, the compounds of formula (I) are characterised
in that by their versatility in the therapeutic field. Particular mention
should be made of the possible applications for which the compounds of
formula (I) according to the invention are preferably used on the basis
of their pharmaceutical efficacy as tyrosine inhibitors.

[0488] The compounds of general formula (I) according to the invention
thus inhibit signal transduction by tyrosine kinases, as demonstrated by
the example of the human EGF receptor, and are therefore useful for
treating pathophysiological processes caused by hyperfunction of tyrosine
kinases. These are e.g. benign or malignant tumours, particularly tumours
of epithelial and neuroepithelial origin, metastasisation and the
abnormal proliferation of vascular endothelial cells (neoangiogenesis).

[0489] The compounds according to the invention are also useful for
preventing and treating diseases of the airways and lungs which are
accompanied by increased or altered production of mucus caused by
stimulation of tyrosine kinases, e.g. in inflammatory diseases of the
airways such as chronic bronchitis, chronic obstructive bronchitis,
asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis,
cystic fibrosis, α1-antitrypsin deficiency, or coughs, pulmonary
emphysema, pulmonary fibrosis and hyperreactive airways.

[0490] The compounds are also suitable for treating diseases of the
gastrointestinal tract and bile duct and gall bladder which are
associated with disrupted activity of the tyrosine kinases, such as may
be found e.g. in chronic inflammatory changes such as cholecystitis,
Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal
tract or such as may occur in diseases of the gastrointestinal tract
which are associated with increased secretions, such as Menetrier's
disease, secreting adenomas and protein loss syndrome.

[0491] In addition, the compounds of general formula I and the
physiologically acceptable salts thereof may be used to treat other
diseases caused by abnormal function of tyrosine kinases, such as e.g.
epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia
(BPH), inflammatory processes, diseases of the immune system,
hyperproliferation of haematopoietic cells, the treatment of nasal
polyps, etc.

[0492] By reason of their biological properties the compounds according to
the invention may be used on their own or in conjunction with other
pharmacologically active compounds, for example in tumour therapy, in
monotherapy or in conjunction with other anti-tumour therapeutic agents,
for example in combination with topoisomerase inhibitors (e.g.
etoposide), mitosis inhibitors (e.g. vinblastine), compounds which
interact with nucleic acids (e.g. cisplatin, cyclophosphamide,
adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of
metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons),
antibodies, etc. For treating respiratory tract diseases, these compounds
may be used on their own or in conjunction with other therapeutic agents
for the airways, such as substances with a secretolytic (e.g. ambroxol,
N-acetylcysteine), broncholytic (e.g. tiotropium or ipratropium or
fenoterol, salmeterol, salbutamol) and/or anti-inflammatory activity
(e.g. theophylline or glucocorticoids).

[0493] For treating diseases in the region of the gastrointestinal tract,
these compounds may also be administered on their own or in conjunction
with substances having an effect on motility or secretion. These
combinations may be administered either simultaneously or sequentially.

Formulations

[0494] The compounds according to the invention may be administered by
oral, transdermal, inhalative, parenteral or sublingual route. The
compounds according to the invention are present as active ingredients in
conventional preparations, for example in compositions consisting
essentially of an inert pharmaceutical carrier and an effective dose of
the active substance, such as for example tablets, coated tablets,
capsules, lozenges, powders, solutions, suspensions, emulsions, syrups,
suppositories, transdermal systems etc. An effective dose of the
compounds according to the invention is between 0.1 and 5000, preferably
between 1 and 500, more preferably between 5-300 mg/dose for oral
administration, and between 0.001 and 50, preferably between 0.1 and 10
mg/dose for intravenous, subcutaneous or intramuscular administration.
For inhalation, according to the invention, solutions containing 0.01 to
1.0, preferably 0.1 to 0.5% active substance are suitable. For
administration by inhalation the use of powders, ethanolic or aqueous
solutions is preferred. It is also possible to use the compounds
according to the invention as a solution for infusion, preferably in a
physiological saline or nutrient saline solution.

[0495] The compounds according to the invention may be used on their own
or in conjunction with other active substances according to the
invention, optionally also in conjunction with other pharmacologically
active substances. Suitable formulations include, for example, tablets,
capsules, suppositories, solutions, syrups, emulsions or dispersible
powders. Corresponding tablets may be obtained for example by mixing the
active substance(s) with known excipients, for example inert diluents,
such as calcium carbonate, calcium phosphate or lactose, disintegrants
such as maize starch or alginic acid, binders such as starch or gelatine,
lubricants such as magnesium stearate or talc and/or agents for delaying
release, such as carboxymethyl cellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise several layers.

[0496] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used for
tablet coatings, for example collidone or shellac, gum arabic, talc,
titanium dioxide or sugar. To achieve delayed release or prevent
incompatibilities the core may also consist of a number of layers.
Similarly the tablet coating may consist of a number of layers to achieve
delayed release, possibly using the excipients mentioned above for the
tablets.

[0497] Syrups containing the active substances or combinations thereof
according to the invention may additionally contain a sweetener such as
saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a
flavouring such as vanillin or orange extract. They may also contain
suspension adjuvants or thickeners such as sodium carboxymethyl
cellulose, wetting agents such as, for example, condensation products of
fatty alcohols with ethylene oxide, or preservatives such as
p-hydroxybenzoates.

[0498] Solutions for injection are prepared in the usual way, e.g. with
the addition of preservatives such as p-hydroxybenzoates, or stabilisers
such as alkali metal salts of ethylenediamine tetraacetic acid, and
transferred into injection vials or ampoules.

[0499] Capsules containing one or more active substances or combinations
of active substances may for example be prepared by mixing the active
substances with inert carriers such as lactose or sorbitol and packing
them into gelatine capsules.

[0500] Suitable suppositories may be made for example by mixing with
carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.

[0504] The active substance is mixed with calcium phosphate, corn starch,
polyvinyl-pyrrolidone, hydroxypropylmethylcellulose and half the
specified amount of magnesium stearate. Blanks 13 mm in diameter are
produced in a tablet-making machine and these are then rubbed through a
screen with a mesh size of 1.5 mm using a suitable machine and mixed with
the rest of the magnesium stearate. This granulate is compressed in a
tablet-making machine to form tablets of the desired shape. [0505]
Weight of core: 230 mg [0506] die: 9 mm, convex

[0507] The tablet cores thus produced are coated with a film consisting
essentially of hydroxypropylmethylcellulose. The finished film-coated
tablets are polished with beeswax. [0508] Weight of coated tablet: 245
mg.

[0510] The active substance, lactose and starch are mixed together and
uniformly moistened with an aqueous solution of the polyvinylpyrrolidone.
After the moist composition has been screened (2.0 mm mesh size) and
dried in a rack-type drier at 50° C. it is screened again (1.5 mm
mesh size) and the lubricant is added. The finished mixture compressed to
form tablets. [0511] Weight of tablet: 220 mg [0512] Diameter: 10 mm,
biplanar, facetted on both sides and notched on one side.

[0514] The active substance mixed with lactose, corn starch and silica is
moistened with a 20% aqueous polyvinylpyrrolidone solution and passed
through a screen with a mesh size of 1.5 mm. The granules, dried at
45° C., are passed through the same screen again and mixed with
the specified amount of magnesium stearate. Tablets are pressed from the
mixture. [0515] Weight of tablet: 300 mg [0516] die: 10 mm, flat

[0524] The distilled water is heated to 70° C. The methyl and
propyl p-hydroxybenzoates together with the glycerol and sodium salt of
carboxymethylcellulose are dissolved therein with stirring. The solution
is cooled to ambient temperature and the active substance is added and
homogeneously dispersed therein with stirring. After the sugar, the
sorbitol solution and the flavouring have been added and dissolved, the
suspension is evacuated with stirring to eliminate air. [0525] 5 ml of
suspension contain 50 mg of active substance.

[0533] The active substance and benzalkonium chloride are dissolved in
ethanol/water (50/50). The pH of the solution is adjusted with 1N
hydrochloric acid. The resulting solution is filtered and transferred
into suitable containers for use in hand-held nebulisers (cartridges).

[0534] Contents of the container: 4.5 g

Patent applications by Birgit Jung, Laupheim DE

Patent applications by Frank Himmelsbach, Mittelbiberach DE

Patent applications by Ralf Lotz, Schemmerhofen DE

Patent applications by BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Patent applications in class With additional active ingredient

Patent applications in all subclasses With additional active ingredient